PROCESS FOR THE PRODUCTION OF 14{62 , 18- and 5{62 , 19-(EPOXYETHANOIMINO)-STEROIDS

ABSTRACT

A new process for the production of 14 Beta , 18- and 5 Beta , 19-(epoxyethanoimino)-steroids is provided, which comprises reacting corresponding thiolactams, i.e. 2&#39;&#39;-thioxo-14 Beta , 18and 5 Beta , 19-(epoxyethanoimino)-steroids, with Raney Nickel in an organic solvent. The 2&#39;&#39;-thioxo-compounds are in turn obtained from corresponding lactams, i.e. 2&#39;&#39;-oxo-14, 18- and 5 Beta , 19(epoxy-ethanoimino)-steroids, by heating with phosphorus pentasulfide in pyridine. By a specific embodiment 1&#39;&#39;-methyl-2&#39;&#39;thioxo-3 Beta -methoxy-3 Alpha , 9 Alpha -epoxy-11 Alpha , 20 xi -diacetoxy-14 Beta , 18-(epoxyethanoimino)-5 Beta , 17 Alpha pregnane is converted into 1&#39;&#39;-methyl-3 Beta -methoxy-3 Alpha , 9 Alpha -epoxy-11 Alpha , 20 xi -diacetoxy-14 Beta , 18(epoxyethanoimino)-5 Beta , 17 Alpha -pregnane.

United States Patent [191 Wehrli et a].

[ June 18,1974

[54] "pnociiss FonTiiE PRODUCTION OF 11B,

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: Dec. 8, 1971 [21] Appl. No.: 206,170

[30] Foreign Application Priority Data Dec. 14, 1970 Switzerland18469770 Dec. 14, 1970 Switzerland", l858 5/70 [52] U.S. Cl 260/239.55R, 260/239.57,

260/397.45, 260/397.5 [51] Int. CL. C07c 173/00 [58] Field of Search260/239.55, 239.5

[56] References Cited UNITED STATES PATENTS 3,706,737 12/1972 Wehrli eta]. 260/239.55 R

Primary ExaminerE1bert L. Roberts Attorney, Agent, or Firm-Joseph G.Kolodny [57] ABSTRACT A new process for the production of 14B, 18- and5,8, 19-(epoxyethanoimino)-steroids is provided, which comprisesreacting corresponding thiolactams, i.e. 2'-

thioxo-l4fi, 18- and 5B, l9-(epoxyethanoimino)- steroids, with RaneyNickel in an organic solvent. The 2'-thioxo-compounds are in turnobtained from corresponding lactams, i.e. 2'-oxo-l4, 18- and 5B, 19-(epoxy-ethanoimino)-steroids, by heating with phosphorus pentasulfide inpyridine. By a specific embodiment- 1-methyl-2-thioxo-3B-methoxy-3a,9a-epoxy- 11a, 20-diacetoxy-14B, l8-(epoxyethanoimino)-5B, l7a-pregnaneis converted into. l'-methyl-3B- methoxy-3a, 9a-epoxy-l 1a,20-diacetoxy-14B, l8- (epoxyethanoimino)-5B, l 7a-pregnane.

14 Clainis, No Drawings PROCESS'FOR THE PRODUCTION OF 14B, 18-

AND S B, l9-(EPOXYETHANOIMINO)-STEROIDS DETAILED DESCRIPTION The objectof the present invention is a process for the production of steroidcompounds of the general Formula I, 1

wherein R, has the meaning given under formula I, R represents aprotected oxo radical, or an esterified or etherified hydroxyl group anda hydrogen atom,

R represents a protected oxo radical, or an esterified or etherifiedhydroxyl group and a hydrogen atom, or an etherified hydroxyl group andtogether with R, an epoxy radical.

R and R each independently represent a protected oxo radical, or anesterified or etherified hydroxyl group and a hydrogen atom, or twohydrogen atoms, or. when occurring at a double bond, one hydrogen atom.

R represents an aor B-oriented hydrogen atom,

R represents an a-oriented hydrogen atom, an a-oriented hydroxyl group,or together with R, an epoxy radical, and

R represents an aor B-oriented hydrogen atom, or

an esterified or etherified hydroxyl group,

whereby double bonds may be present in the positions 5, 7, 9 (l l) and16 corresponding to the dotted lines with the elimination of R R and/orR or to formula lb,

wherein R, has the meaning given under formula I, and

- five carbon atoms and is particularly a methyl group,

further, e.g. an ethyl group, a n-propyl group, an iso propyl group, abutyl groupor pentyl group. The aforementioned esterified hydroxylgroups in 20-position of the compounds of the formula la or in thel7B-position of the compounds of the formula lb respectively are derivedfrom lower alkanoic acids such as: acetic acid, propionic acid, butyricacid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid offormic acid; or from pyrrole carboxylic acids and alkyl-substitutedpyrrole carboxylic acids such as 2,4,5-trimethylpyrrole-3- carboxylicacid, 2,4-dimethylpyrr0le-3-carboxylic acid or2-ethyl-4-methylpyrrole-3-carboxylic acid. Esterified hydroxyl groups inthe positions 3, 7, l 1 and/or 17 of the formula Ia or in the furtherpositions of the compounds-of the formula lb are derived from loweralkanoic acids, e.g. from the afore-mentioned lower alkanoic acids. I

Suitable etherified hydroxyl groups in the positions 3, 2 0, 7, 11and/or l7 of the compounds of the formula la or in the position 173 andfurther positions of the compounds offthe formula lb are, in particular,those which are derived from lower alkanols such as methyl alcohol,ethyl alcohol, propyl alcohol, isopropyl alcohol, or from the butyl oramyl alcohols. Suitable as etherified hydroxyl group, are, for example,also the (tetrahydro-ZH-pyran-Z-yl)-oxy group, as well as the benzyloxygroup and the triphenyl-methoxy group, the4-methoxy-tetrahydro-pyran-4-yloxy group and the l,-l-methoxy-cyclohexyl-l-yloxy group. Protected oxo radicals in the 3-,20, 7- and/or 1 l-p0sitions of the compounds of the formula Ia or in thel7-positi0n and further positions of the compounds of the formula Ib areketal groupings which are derived from lower alkanediols of from loweralkanols.

The lower aliphatic hydrocarbon radical in position may be saturated orunsaturated, Preferably, such a radical contains one to four carbonatoms and is in particular, a methyl or ethinyl group or further, e.g.,an ethyl, propyl, vinyl, allyl, 2-methylallyl, l-propinyl or 2-propinylgroup.

The compounds of the general formula I possess valuable pharmacologicalproperties, especially blood-circulation-promoting activity. Compoundsof the general formula in selectively raise the permeability of muscleand nerve membranes for sodium ions. The resulting increase of influx ofsodium ions causes an acceleration of depolarization and thus also ofmuscle contraction, Since according to recent evidence cardio-activesubstances of the digitalis-strophanthin type hinder the active transferof sodium ions out of the muscle fibers by blocking thetransfer-adenosin triphosphate-ase of the membranes thus likewiseincreasing the sodium concentration, and accelerating depolarization andmuscle contraction, the compounds of general formula I lead ultimately,via the different mechanism already mentioned, to therapeutic effectswhich are similar to those of the cardio-active digitalis substancessuch as strengthening of the systole and of the minute volume of theheart.

The compounds of the general formulae la and lb are also valuableintermediate products for the preparation of other pharmacologicallyeffective compounds with similar properties. Some possibilities for thefurther conversion of compounds of the general formula la are indicatedhereinafter.

Of particular importance as pharmacologically active substances and asintermediate products therefor are the compounds of the general formulalc and R R R R R R and R have the meaning given under formula l or inrespectively,

whereby double bonds can be present in the positions 5, 7 and 16corresponding to the dotted lines, with the elimination of R and Raccordingly.

The process for the production the compounds of general formula 1 of thepresent application and of their acid addition salts is characterised inthat a compound of the general formula ll wherein R,, Y and Z have themeaning given for formula l, is reacted with Raney-Nickel in an organicsolvent and if desired. the compound of the general formula I obtainedin converted into an addition salt with an inorganic or organic acid.The reaction according to the invention with Raney nickel is performed,for example, at temperatures of between 0 and 50C, preferably at roomtemperature, in an organic solvent such as, e.g. ethanol, methanol oracetone. The Raney nickel is preferably used in an appreciable excess,ie the amount thereof corresponds to the 2- to 20-fold amount by weightof the starting material of general formula II. If the starting materialcontains double bonds it is of advantage to reducethe activity of theRaney nickel by treatment thereof with acetone before the reaction,and/or to perform the subsequent reaction in acetone.

The compounds of the general formula II are new compounds which areembraced either by the narrower general formula Ila wherein R to R havethe meanings given under formula l or la respectively and the doublebonds mentioned there can be present, or by the narrower general formulallb wherein R represents a lower alkyl radical, hydrogen or the phenylgroup and R to R have the meanings given under formula la, wherebydouble bonds may be present in h Positions 9 l l and 16 Corresponding e)reacting the compound of the general formula VIII t the ted i e t theelimination of s, 1 with a reactive functional derivative of ahalogenoand/or R in order to cleave off the acyl group acetic acid inthe presence of an acid binding agent CO-R to obtain a compound of thegeneral formula IX, b) oxidising the compound obtained of the generalformula IV to convert the l8-hydroxy group into the l8-oxo radi- V cal;wherein c) reacting the oxidation product of the general for- Xrepresents a halogen atom, e.g. chlorine, bromula V mine or iodine, and

R, to R have themeanings given under the for- 4 mula l or larespectively and the double bonds I mentioned there can be present,

1) then cyclising the compound of the general fori g R mula IX byreaction with a basic metal compound l I a in the presence of an organicsolvent which is inert A R i and/or one containing hydroxyl groups, to alactam 0H of the general formula X, R1 '-R| with a compound of thegeneral formula VI,

H NR,

wherein R has the meaning given under formula I and, if necessary,reacylating hydroxyl groups in R R R and/or R, which have been set free;

d) then reducing the reaction product of the general formula Vll whereinR, to R have the meanings given under formula l or la respectively andthe double bonds mentioned there can be present, and

g) heating the lactam of the general formula X with v11 phosphoruspentasulfide in an organic solvent.

The partial hydrolysis, step (a) of the above-defined a reactionsequence, is preferably performed by reacting by means of a complexhydride to the compound of the the compound of general Formula lll withabout the general formula Vlll equimolar or equivalent amount of a basicsubstance in an organic or organic/aqueous solvent at temperaturesbetween about 20 and 120C or the boiling tempera- B ture of the reactionmedium. For example, the compound of general Formula lll is heated orboiled for a short period with about an equivalent amount of sodium,potassium or lithium bicarbonate in alkanolic- /aqueous solution, e.g.in hydrous methanol or ethanol: or a compound of general Formula III isreacted at room temperature or with heating with the equimolar amount ofan alkali metal alkoxide, e.g. with sodium (vm) methoxide in a loweralkanol such as methanol, ethanol or butanol. Weakly basic reagents suchas the aforementioned alkali bicarbonates can also be used in excesswhen the temperature and length of the reaction are so chosen that whenthe hydrolysis is interrupted, only the l8-hydroxyl group has been setfree. Suitable as acyl groups COR, is e.g., acetyl, formyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl or benzoyl groups. InR; as well as in R R and R there may be acyl groups identical with ordiffering from COR, but in the latter case COR, should be more readilysplit off than the other acyl groups.

The possibility of partially hydrolyzing the polyacyloxy compound ofgeneral Formula Ill in order to protect the 20-hydroxyl group during thesubsequent oxidation of the lS-hydroxyl group which has been set free,is an important prerequisite for the success of the entire reactionsequence leading from the compounds of general Formula lll to thecompound of general Formula II and thus also for the production of thefinal products of general Formula I. That the compounds of generalFormula lll could be partially hydrolyzed, was in no way predictable,for according to A. L. Nussbaum, F. E. Carlon, E. P. Oliveto, E..Townley, P. Kabasakalian and D. H. R. Barton, Tetrahedron 18 (1962),373-378, especially the upper part of page 375, the selective protectionof one or the other of the two hydroxyl groups in the positions 18 and20 in -dihydroxy--di-hydroxy-4-pregnen-3-one is not possible.

The oxidation according to step (b), in which the 18- hydroxy group isconverted into the 0x0 radical thus forming an aldehyde group, can beperformed e.g. by

means of a 6-valent chromium compound, e.g. with a slight-excess of asolution of chromium trioxide in hydrous sulphuric acid in acetone asreaction medium in the cold, furthermore also with chromium trioxide inpyridine. When ketal groups and/or a 3B-alkoxy group together with a30:, 9a-epoxy radical are present, special care should be taken, whenusing chromium trioxide/sulphuric acid solutions, to maintain a lowtemperature, preferably at or below 0C.

The reaction of the compounds of general Formula V according to step (c)with a compound of general Formula VI such as methylamine, ethylamine,npropylamine, isopropylamine, n-butylamine, isobutylamine, benzylamineor ammonia, takes place e.g. at temperatures between about 80 and 150Cin an inert organic solvent such as benzene, toluene, methanol, ethanolor butanol, and if necessary in a closed vessel, depending on theboilingpoint of the compound of gen eral'Formula Vl and of the solvent as wellas on the reaction temperature. The compound of general Formula V] ispreferably used in excess and can optionally be used as sole reactionmedium. in the reaction according to the process, aminolysis of acyloxygroups which readily split off also occurs. The hydroxyl groups whichhave been set free are then optionally again acylated in the same manneras given for the hydroxyl groups of the end products, for example withan acetanhydridelpyridine mixture at room temperature. If desired, thehydroxyl groups which have been set free can be left AcO- b follows:

8 free for the next steps and reacylated only after step e) or f).

The following reduction, step (d), of the imino compounds of generalFormula Vll is e.g. performed with sodium boro-hydride in aqueousmethanol at temperatures between about 0 and 70C, preferably at roomtemperature.

For the introduction of the halogeno-acetyl group into the secondary orprimary l8-amino group, step (e), for example, a halogeno-acetyl halideor halogenoacetanhydride, such as chloro-acetyl chloride, bromoacetylchloride, bromo-acetyl bromide, chloroacetanhydride,bromo-acetanhydride, in an inert organic solvent, e.g. a hydrocarbon orhalogenated hydrocarbon such as benzene or chloroform, is employed,whereby there is added as acid-binding agent, e.g., an aqueousalkali-metal hydroxide solution as second phase, as well as a solidinorganic basic substance such as potassium or sodium carbonate, or anorganic base such as N-ethyl-diisopropylamine, triethylamine, sym.collidine or pyridine. The reaction is preferably performed attemperatures between 0 and about C, whereby an excess ofhalogeno-acetylating agent should be avoided when there are freesecondary hydroxyl groups present in the starting material.

For the cyclisation of the compounds of the above general formula lXaccording to step f), metal hydroxides are preferably used as basicmetal compounds, such as: silver hydroxide, sodium or potassiumhydroxide solution, basic metal salts such as sodium and potassiumcarbonate, or sodium and potassium bicarbonate, alkali metal alcoholatessuch as, e.g. sodium methylate, sodium ethylate orpotassium-tert.butylate, metal hydrides such as sodium hydride, calciumhydride or lithium aluminium hydride. The solvents used for the reactionaccording to the process are, preferably, aliphatic, cyclic or aromatichydrocarbons, especially benzene or toluene, ethers such as, e.g.diethyl ether, tetrahydrofuran, dioxane, or also dimethylsulphoxide,dimethylformamide and/or. alcohols such as, e.g. methanol, ethanol ortert.butanol. An advantageous embodiment of the cyclisation is thereaction of the starting materials with sodiumhydride in a mixture,preferably 1:], of benzene and tetrahydrofuran in the presence ofcatalytic amounts of an alcohol, especially methanol or ethanol.

The conversion of the lactams of the general formula X into thecorresponding thiolactams of the general fonnula Ila is performed byheating with phosphorus pentasulfide to temperatures of ca. l00-l50C inan inert organic solvent. Preferably, the lactams of the general formulaX are refluxed in a solvent of suitable boiling point, such as, e.g.dioxane, toluene, xylene, collidine and, in particular, pyridine for ca.half an hour to several hours.

Compounds of the general formula II] can be produced from various knownstarting materials by sequences with a few exceptions of reactions knownper se. Two examples of such reaction sequences are as embraced byFormula III According to the first reaction sequence, thestartingcompound is 3B-acetoxy-20B-hydroxy-Sa-pregnane (l), which can besubstituted as defined. Compounds of this type are described in theliterature. By oxidation with lead tetraacetate in the presence ofiodine in cyclohexane, and re-oxidation with CrO and subsequent reactionwith silver acetate followed by an aftertreatment with silica gel/water,is obtained 3B-acetoxyl 8,20-oxido-2O {-hydroxy-Sa-pregnane (2).Treatment of (2) with acetic anhydride/Pyridine, at elevatedtemperature, yields 3/3,]8-diacetoxy-20-oxo-Sa-pregnane (3), which canbe converted by bromination with pyridinium hydrobromide-perbromide andsubsequent dehydrobromination with dimethyl formamide into 3-,B,l8-diacetoxy-20-oxo-A -a-pregnene (4). A repeated bromination withN-bromo-succinimide and dehydrobromination with sodium iodide in acetoneyield 313, l 8-diacetoxy-20-oxo-A -Sa-pregnadiene (5). Epoxidation withp-nitroperbenzoic acid yields 3- B, 18-diacetoxy-14B,l5B-epoxy-20-oxo-A-5apregnene (6), which is converted bycatalytic hydrogenation in ethanol, in the presence of palladium onbarium sulphate, into 3B,lS-diacetoxy-14B-hydroxy-20-oxo-5a,l7a-pregnane (7). Reduction withlithiumaluminium-tritert.butoxyhydride subsequently leads to 3B, 18-diacetoxy- 1 4,8,20 -dihydroxy-5a, l 7a-pregnane (8), which can beacetylated to 33,18,20 if-triacetoxyl4,B-hydroxy-5a,17a-pregnane (9).The latter is embraced by the general Formula Ill.

In the second reaction sequence, the starting compound, (20R)3-ethylenedioxy-20-hydroxy-A pregnadien-18-acid lactone-( 20) 1 l whichis also known, is first reduced with lithium aluminium hydride to the18,20-dihydroxy compound. The subsequent cleaving of the 3-ethylenedioxygroup with a little hydrochloric acid in acetic acid/methanol leads to(20R)- 3-oxo-l 8,20-dihydroxy-A "-pregnadiene 12), which is hydrogenatedwith the calculated amount of hydrogen in the presence of apalladium/charcoal catalyst to (20R)-3oxo-18,20-dihydroxy-N -5B-pregnene (l3). Partial acetylation thereof with acetanhydride/pyridineat room temperature leads to (20R)- 3-oxol 8-acetoxy-20-hydroxy-A"-SB-pregnene 14), which is oxidized with chromium trioxide/sulphuricacid in acetone to 3,20-dioxo-18-acetoxy-A -5B- pregnene (l5 Ontreatment of the latter with osmium tetroxide in pyridine at roomtemperature and darkness, after several days there is surprisinglyobtained 313,1 1a-dihydroxy-3a,9a-epoxy-1 8-acetoxy-2O-oxo-5B -pregnane(l6). This is in contrast to the statement made by L. F. Fieser inSteroids, Reinhold Publishing Corporation, New York, 1959, page 669,according to which A -5B-steroids cannot be reacted with osmiumtetroxide.

The cyclic hemiketal (16) is first converted with methanolic hydrogenchloride to the ketal and then acetylated with acetanhydride/pyridine toobtain 33- methoxy-3a,9a-epoxy-1 101,1 S-diacetoxy-ZO-oxo-SB- pregnane(17). On bromination with N-bromosuccinimide in l7-position and cleavinghydrogen bromide by means of lithium carbonate/lithium bromide,3B-methoxy-3a,9a-epoxy-1 1a,! 8-diacetoxy-20-oxo- A -SB-pregnene (18) isobtained. Repetition of the two latter reactions yields3B-methoxy-3a,9a-epoxyl 101,18-diacetoxy-2O-oxo-A" -SB-pregnadiene (19).Treatment thereof with p-nitro-perbenzoic acid in chloroform/methanolleads to 3B-methoxy- 301,901: l 4/3, l SB-diepoxy-l101,18-diacetoxy-20-oxo-A' SB-pregnene (20), from which, by thoroughhydroge nation in the presence of palladium/barium sulphate catalyst inethanol, 3B-methoxy-3a,9a-epoxy-1101,18-diacetoxy-14B-hydroxy-20-oxo-5BJ 7a-pregnane (21 is obtained. This isfinally converted by reduction with sodium boro-hydride inmethanol/water and subsequent acetylation with acetanhydride/pyridineinto 38- methoxy-3a,9a-epoxy-l la, 1 8,20f-triacetoxy- 1 4B-hydroxy-5B,l7a-pregnane (22), which is embraced by the general Formula111.

The above reaction sequences can also be performed analogously withcompounds which instead of the 3- acetoxy or 3-ethylene-dioxy group haveother protected hydroxyl groups or 0x0 radicals falling under thedefinition for R Analogous to the second reaction sequence, the startingmaterials having a protected functional group corresponding to thedefinition of R 7-position can also be converted into compounds ofgeneral Formula lll, whereby the functional group in 7-position can beleft or can be used to introduce a double bond into the 7,8-position. Itis, e.g., likewise possible to reintroduce a double bond into thel6,17-position analogously to the conversion of the compound (17) intothe compound (18) in the second reaction sequence.

The compounds of the general formula llb can be prepared by cyclisationof a compound of the general formula Xl wherein X represents a halogenatom, e.g. chlorine, bromine or iodine, and R, and R have the meaningsgiven under formula l or lb respectively, and the substituents anddouble bonds mentioned there can be present, which cyclisation iseffected by reaction with a basic metal compound in the presence of anorganic solvent which is inert and/or one containing hydroxyl groupsanalogously to step I) of the reaction sequence mentioned hereinbeforeand leads to a lactam of the general formula Xll (in N l wherein R, andR have the meanings given under formula l or lb respectively and thesubstituents and double bonds mentioned there can be present, andheating the lactam of the general formula X11 in an organic solventanalogously to step g) of the reaction sequence mentioned hereinbefore.

The compounds of the general formula X] to be used as starting materialscan be obtained, for example, ac-

OAc /\1 l pound is 3-oxo-17B, l9-diacetoxy-A -androstene( l which can besubstituted as defined. Compounds of this type are described in theliterature. By oxidation with hydrogen peroxide in an alkaline mediumand subsequent acetylation is obtained the corresponding 3-oxo-4B,5B-epoxyl 7,8, 1 9-diacetogry-androstane( 2) which yields, aftertreatment with hydrazine hydrate and acetic acid in ethanol,SB-hydroxy-l7B,l9-diacetoxy- A -androstene(3). By hydrogenation, eg inthe presence of platinum oxide in ethanol, B-hydroxy-l7l3,l9-diacetoxy-androstane (4) is obtained and from that is obtained, bypartial hydrolysis with methanolicaqueous sodium bicarbonate solution,56,19- dihydroxyl 7B-acetoxy-androstane( 5 I The latter is converted, byboiling with silver carbonate on Celite in abs. benzene, into theSB-hydroxy-UB- acetoxy-l9-oxo-androstane(6), which is reacted withmethylamine to give 5/3-hydroxy-l7B-acetoxy-l9(methylimino)androstane(7). Reduction of the latter with sodiumborohydride in methanol/water yields 5/3- hydroxyl 7B-acetoxyl 9-(methylamino)- androstane(8), which is acylated with chloroacetylchloride in chloroform, in the presence of sodium hydroxide solution, to5B-hydroxy-l7B-acetoxy-l9-(N- methyl-Z-chloroacetamido)-androstane(9),usable as starting'material of the general formula XI.

The above reaction sequence can be performed, in an analogous manner,with compounds containing in the l7-position, instead of the l7B-acetoxygroup, another functionally modified hydroxyl group within the cordingto the following reaction pattern: 5 scope of the above given definitionfor R It is also pos- A00 A00 AcO 9 NH NHrH O 1 0H HO-Ac 2) 01H50H H 3)lH /PtOz w, i, v ,7 m, a soH oAc 0A0 0A0 I l I HN R R0 NBB'HS A iooa onCelite $11 8) H H v 7) GHQ-NHL 6) s 5 NaHCO; 4) R=NCH; 11:0 0 R=H ornoHmo R=Ac 01cm:

CHClz/Base in H1O sible to start, however, with analogous compoundshaving a ketalised l7-oxo radical, in order to obtain starting materialsof the general formula Xl having a protected l7-'oxo radical.

Belonging to the object of the invention are also the new startingmaterials for the present process corresponding to the general formulaII and the narrower general formulae lla and llb.

As mentioned above, the compounds of the general formula I can also beused as intermediate products for further syntheses. Hydroxyl groups canbe set free, eg from lower alkanoyloxy groups occuring in the groupingsR R,,, R and, particularly, in R of the compounds of the generalformulae la and lo or in the grouping R of the compounds of the generalformula lb respectively, by alkaline hydrolysis. Oxo radicals protectedby ketal groupings occuring as R R R and/or R or as R respectively canbe set free by treatment with acids under mild conditions, e.g. withmixtures of percent aqueous perchloric acid and glacial acetic acid atroom temperature. Under the same conditions, an alkoxy group in3B-position occuring with a 3a,9a-epoxy radical is converted into thehydroxyl group. Liberated oxo radicals can be reduced to hydroxylgroups, e.g., by means of complex hydrides such as sodium borohydride ortri-tert-butoxy-lithium aluminium hydride, e.g. in tetrahydrofuran.Liberated hydroxyl groups can be oxidised to oxo groups, by means of theOppenauer reaction or with the aid of compounds of 6-valent chromium,e.g. chromium trioxide in pyridine. Liberated hydroxyl groups can beesterified in a known manner, e.g. by treatment with an acid halide oracid anhydride derived from a lower alkanoic acid, in the presence of atertiary base such as pyridine. Esters of optionally alkyl-substitutedpyrrole carboxylic acids and of products of the hydrolysis of compoundsof the general formula la, which products contain a free hydroxyl groupin position and preferably a double bond in position 16, 17, areobtained, in particular, by reaction of such 20-hydroxy compounds withmixed anhydrides of optionally alkyl-substituted pyrrole carboxylicacids and lower alkoxyfonnic acids at room temperature in a biphasicsystem consisting of mar ganic solvent immiscible with water, e.g.methylenechloride, chloroform or benzene, and aqueous sodium hydroxideor potassium hydroxide solution.

Optionally, the new compounds of the general Formula 1 obtainedaccording to the invention are converted in the usual manner into theiracid addition salts with inorganic and organic acids. For example, to asolution of a corresponding compound of the general Formula 1 in anorganic solvent such as benzene, diethyl ether, methanol, ethanol oracetone, is added the acid desired as the salt component, or a solutionof the acid, and the salt, which has precipitated immediately or afterthe addition of a second organic liquid such as, e.g. diethyl ether tomethanol, is separated. Liberation of the bases from their acid addition salts is likewise performed in the usual manner by reaction withbasic substances such as, e.g. sodium carbonate or sodium bicarbonate.

For use as active substances for pharmaceutical preparations it ispossible to employ, instead of free basic compounds of the generalFormula 1, pharrnaceutically acceptable acid addition salts thereof,i.e. salts with such acids, the anions of which exhibit, in the case ofthe dosages in question, either no inherent pharmaco logical action or adesired one. Furthermore, it is of advantage if the salts to be used asactive substances crystallize well and are not, or only slightly,hygroscopic. For salt formation with compounds of the general Formula 1suitable for the purpose, it is possible to use, e.g. hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulphonic acid, B-hydroxyethanesulphonic acid, acetic acid,malic acid, tartaric acid, citric acid, lactic acid, succinic acid,fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylaceticacid, mandelic acid, embonic acid or 1,5-naphthalene-disulphonic acid.The pharmacologically active compounds of the general formula 1 of thepresent application or their pharmaceutically acceptable acid additionsalts can be combined with pharmaceutical carriers to yieldpharmaceutical preparations for application in human or veterinarymedicine.

Used as carriers are organic or inorganic substances which are suitablefor enteral administration, e.g. oral, parenteral, or topicaladministration. Suitable for the formation thereof are such substanceswhich do not react with the new compounds, such as e. g. water,gelatine, lactose, starch, magnesium stearate, talcum, vegetable oils,benzyl alcohols, rubber, polyalkylene glycols, vaselines, cholesterolandother known medicament-carriers. The pharmaceutical preparations canbe in solid form, e.g. as tablets, dragees or capsules; or in liquid orsemi-liquid fomt as solutions, suspensions,

emulsions, ointments or creams. Optionally, these pharmaceuticalpreparations are sterilized and/or they contain auxiliaries such aspreservatives, stabilizers, wetting or emulsifying agents, salts formodifying the osmotic pressure, or buffers. They can also contain othertherapeutically valuable substances. The new substances can also serveas starting products for the production of other valuable compounds.

The compounds of the general Formula I can also be used as animal-feedadditives.

The invention is described in more detail in the following examples;these in no way limit, however, the scope of the invention. Thetemperatures are given in de grees Centigr ade. The rotations aremeasured in chloroform; concentrations are given in parenthesis. The IRspectra are measured in chloroform, or in another solvent given inparenthesis; the absorption bands are given in cm. The UV spectra aretaken in ethanol; absorption maxima are stated in nm, -values are inparenthesis.

Ce'lite is a tradename of the Johns-Manville International Corp., NewYork.

EXAMPLE 2 g 7 An amount of mg of l'-methyl-2-thioxo-3B-methoxy-3a,9a-epoxy-l 1a,20-diacetoxy-l4B,18- (epoxyethanoimino)-5fl,l7a-pregnane (see Example 5) is reacted, analogously to Example 1, with lg of Raney nickel. The obtained crude product is chromatographed onsilica gel in a cyclohexane/chloroform/methanol/triethylamine mixture16:4: 1 :l'). in this way are obtained 68 mg of amorphousl'-methyl-3B-methoxy- 3a,9a-epoxy-1 1a,20-diacetoxy- 1 4B, 1 8-(epoxyevthanoimino)-5B, l7a-pregnane. IR: 1725, 1250, 1100, 1005, 960.

I g EXAMPLE3 An amount of 50 mg of 1-methyl-3/3-methoxy- 3a,9a-epoxy-l1a,20-diacetoxy-143,18-(epoxyethanoimino)-5B,17a-pregnane (see Example2) is refluxed in 5 ml of boiling 5 percent methanolic potassiumhydroxide solution for 2 hours. The reaction solution is diluted withethyl acetate, washed with saturated aqueous sodium chloride solution,dried with magnesium sulphate, and concentrated in vacuo. By this meansare obtained 38 mg of l'-methy1-3B-methoxy- 3a,9a-epoxy-11a,20-dihydroxy- 143,1 8-(epoxyethanoimino)-5B,l7a-pregnane, which meltsat l- 76 after two crystallisations from acetone/water. [01],, 12 (0.25in ethanol). IR: 3560, 3250, 2860, 2800, 1100, 1030, 1000, 955.

EXAMPLE 4 The l '-methyl-2:-thioxo-3B,20-diacetoxy- 143,1 8-

ide solution, dried over magnesium sulphate, and evaporated in vacuum.Thereby obtained are 1.23 g of crude38,18-diacetoxy-l7-bromo-20-oxo-5apregnane which is advantageouslydehydro- (epoxyethanoimmo)-a,l7fl-pregnane used in Example l as startingmaterial can be produced in the following manner:

a. 100 g of lead tetracetate are dried for 2 hours in darkness at roomtemperature. To this are then 5 added 20 g of dry calcium carbonate, andthe mixture is refluxed for one hour, with stirring, in 1700 ml of abs.cyclohexane. To this boiling suspension is thereupon added, withvigorous stirring, a hot solution of 21.8 g of 3B-acetoxy-20B-hydroxy-5qpregnane in 500 ml of absfcyclohexane and 7.7 g of solid iodine; thereaction mixture is then boiled for a further 30 minutes with vigorousstirring, while externally irradiating with a 1,000 Watt inbrominated,without any purification, by three hours boiling in 20 ml of abs.dimethyl formamide under nitrogen. After cooling, the product is dilutedwith ethyl acetate and washed at least five (rises with water. Theorga'aie ha is then dried candescent lamp. A practically completedecolougel. By this means are obtained 860 mg of ration of theiodine-containing reaction mixture is 36,18-diacetoxy--oxo-A*-5a-pregnene which, thereby observed. After cooling, the mixture isfilafter two crystallizations from acetone/hexane, tered through cottonwool, and the filtrate concenmelts at 135. [a| 44 (0.35). IR: 1725,1670, trated in vacuum. The concentration-residue is oxi- 1590, 1250.UV: 238 (e 8920).

dized for 30 minutes in 800 m1 of acetone, at a tem- 20 d. An amount of800 mg of 3B,18-diacetoxy-20-oxoperature of ca. 5, with an excess of an8 N solution A -Sa-pregnene is refluxed for 1 hour, with stirof chromiumtrioxide in 8 N sulphuric acid. 20 ml ring, with 650 mg of'N-bromosuccinimide in 50 ml of isopropanol is then added, the wholediluted of carbon tetrachloride inthe presence of 50 mg of with ethylacetate, and washed until neutral with azo-bis-isobutyronitrile. Themixture is allowed to saturated aqueous sodium chloride solution. Thecrude product obtained after drying and concentration by evaporation ofthe organic phase is refluxed for 3 hours with stirring, in 1,500 ml ofabs. methanol with 25 g of silver acetate. The mixture is afterwardsfiltered through cotton wool, concentrated in vacuum, dissolved inether, and filtered on neutral aluminium oxide (Act. 111). The therebyobtained crude product is chromatographed on 2 kg of silica gel, Merck(grain size 0.05 0.2 mm), which has been previously deactivated with 200m1 of water. With a benzene/ethyl acetate mixture (10:1) are therebyeluted 7.5 g of 3B-acetoxy- 18,20-epoxy-20-hydroxy-Sa-pregnane, M.P. 169(twice recrystallized from acetone/hexane). 1011,, 33 (0.45). IR: 3590,1725, 1250.

b. 1 g of 3B-acetoxy-l8,20-epoxy-20-hydroxy-5apregnane is dissolved in amixture of 7 m1 of pyridine and 7 ml of acetanhydride, and the solutionobtained is heated in a nitrogen atmosphere for 10 hours to 95. Thesolution is allowed to cool; it is then diluted with ethyl acetate, andwashed successively with 2 N aqueous hydrochloric. acid, saturatedaqueous sodium chloride solution, saturated aqueous sodium bicarbonatesolution, and again with saturated aqueous sodium chloride solutionuntil the neutral point is attained. The solution is then dried withmagnesium sulphate, concentrated in vacuum, and chromatographed on the100-fold amount of silica gel which has been deactivated previouslyagain with 10 percent water. With benzene/ethyl acetate mixture (10:1)are thereby firstly eluted 395 mg of 3B,18-diacetoxy-20-oxo-Sci-pregnane; M.P. 107 after two crystallizations from acetone/hexane.[al 70 (0.46). IR: 1740, 1710, 1240 (in CCh). Subsequent fractionsconsisted of 386 mg of unmodified 3B-acetoxy- 18,20-epoxy-20-hydroxy-5a-pregnane.

. An amount of 1.04 g of 313,18-diacetoxy-20-oxo- Sa-pregnane isbrominated in 50 ml of dichloromethane with 1.13 g of 90 percentpyridinehydrobromideperbromide for minutes at room temperature whilststirring is maintained. The reaction mixture is then diluted with ethylacetate, repeatedly washed with saturated aqueous sodium chlorcool; itis'then filtered off from the succinimide which has crystallized out,subsequently washed with carbon tetrachloride, and evaporated in vacuum.The crude bromination product is afterwards boiled for 3 hours with l gof sodium iodide in ml of acetone, the whole concentrated in vacuo toca. 25 ml, diluted with ethyl acetate, and successively washed withaqueous solutions of sodium thiosulphate and sodium chloride. Theorganic phase dried over magnesium sulphate is concentrated in vacuum,and the crude product chromatographed in benzene/ethyl acetate solution(6:1 on silica gel. Thus obtained are 512 mg of oily 33,18-diacetoxy-20-oxo-A" -Sa-pregnadiene. IR: 1735, 1650, 1530, 1240 (CCl UV:312 (e 6250).

. To .976 mg of 313,18-diacetoxy-20-oxo-A -5apregnadiene in 40 ml ofchloroform there are added 488 mg of p-nitroperbenzoic acid, and themixture is stirred in darkness for 19 hours at room temperature. Themixture is then diluted with ethyl acetate, and successively washed withaqueous solutions of potassium iodide, sodium thiosulphate, sodiumchloride, sodium bicarbonate, and again sodium chloride, until theneutral point is attained. The ethyl acetate phase dried with magnesiumsulphate is concentrated in vacuum in a rotary evaporator, and the crudeproduct chromatographed in benzene/ethyl acetate solution (4:1) onsilica gel. In this manner are obtained 550 mg of 313,18-diacetoxy-14B,15B-epoxy-20-oxo-A -5apregnene, M.P. 128l 29 (twicecrystallized from acetone/hexane). [01],, 62 (0.42). IR: 1725, 1670,1600, 1250. UV: 249 (e 8270).

. An amount of 300 mg of 3,3,18-diacetoxy- IR: 3600-3200 broad, 1735,1240 pregnane. (CCL).

hydroxy-20-oxo-5a,l7a-pregnane is stirred in 40 ml of tetrahydrofuranwith 430 mg of lithium aluminium tritert.butoxy-hydride for hours atroom temperature. The excess hydride then decom: posed with 5 percentaqueous acetic acid (ca. 2 ml), diluted with ethyl acetate and washedsuccessively with aqueous solutions of sodium bicarbonate and sodiumchloride until the neutral point is attained. The crude product obtainedafter drying and concentration in vacuum is chromatographed inbenzene/ethyl acetate solution (1:1) on silica gel, whereby 217 mg ofoily 3B,l8-diacetoxy- 14B,20-dihydroxy-5a, 1 7a-pregnane are eluted. IR:3600-3300 broad, 1735, 1240 (CCl h. 150 mg of3B,18-diacetoxy-l4B,20-dihydroxy- 5a,17a-pregnane are allowed to standin ml of pyridine/acetanhydride mixture (1:1) for 16 hours at roomtemperature. The acetylation mixture is then concentrated in vacuum,whereby 155 mg of chromatographically homogeneous oily 35,18,205-triacetoxyl 4B-hydroxy-5a, 1 7a-pregnane are obtained. 1R: 3580, 17351240 (CCl i. An amount of 150 mg of 38,18,20fi-triacetoxy-14B-hydroxy-5a,17a-pregnane is hydrolyzed in a mixture of 32 ml of methanoland 3.5 ml of aqueous 1 percent sodium bicarbonate solution for 5minutes at boiling temperature. The solution is then neutralized withglacial acetic acid, diluted with ethyl acetate, and washed untilneutral with aqueous sodium chloride solution. The crude productremaining behind after concentration by evaporation is chromatographedin benzene/ethyl acetate solution 1:1 on silica gel. Firstly elutedthereby are 38 mg of unmodified starting material, there then follow 67mg of transistion fractions, and afterwards 49 mg of3/3,20-diacetoxy-14B,lS-dihydroxy- 5a,17a-pregnane, M.P. l80181 (twicecrystallized from acetone/hexane). [a| =7 (0.46). IR: 3600-3300, 1730,1240 (CCh).

j. 95 mg of 3B,20-diacetoxy-14B,l8-dihydroxy- 5a,l7a-pregnane areoxidized in 10 ml of acetone at 0 for 2. minutes, with stirring, with anexcess of an 8 N solution of chromium trioxide in 8 N sulphuric acid.The chromium trioxide excess is then decomposed by the addition of 2 mlof isopropanol. The reaction mixture is taken up in ethyl acetate, andwashed with saturated aqueous sodium chloride solution until a neutral,colourless organic phase results. After drying and concentration thereofin vacuum, 85 mg of crude product are obtained, which arechromatographed in benzene/ethyl acetate solution (1:1) on silica gel.Eluted thereby are 65 mg of 3B,20-diacetoxyl4fl-hydroxyl 8-oxo5a, l7a-pregnane which, after two crystallizations from acetone/hexane, meltsat 170171. [0d, 0 (0.42). IR: 3610, 3480,2720, 1735, 1720 1710 (doublebands for the aldehydecarbonyl), 1240 (CCl It. An amount of 270 mg of3B,20-diacetoxy-14B- hydroxy-l8-oxo-5a,l7a-pregnane is heated with 50 mlof methylamine in 50ml of abs. benzene for 15 hours in a bomb tube to120. The mixture is concentrated in vacuo, dissolved in 10 ml ofacetanhydride/pyridine mixture (1:1), allowed to stand for 3 hours atroom temperature, and concentrated in vacuum, whereby 260 mg of 33,205-

diacetoxy-l4/3-hydroxy-18-(methylimino)-5a,17apregnane are obtained. IR:3300 broad, 2760, 1730, 1655, 1240 (CCI The methylimino compoundobtained according to (k) is reduced in 50 ml of methanol with 300 mg ofsodiuniborohydride in 10ml of water at 20 for 20 minutes. To thereaction mixture is then added ethyl acetate, the whole washed untilneutral with saturated aqueous sodium chloride solution, andconcentrated by evaporation, whereby 280 mg of3B,20diacetoxy-14B-hydroxy-l 8-(methylamino)-5a,l7a-pregnane areobtained. IR: 35- 00-2600 broad, 1730, 1250.

m. The methylamino compound obtained according to (l) is dissolvedtogether with 135 mg of chloroacetyl chloride in 50 ml of chloroform. Tothe solution are added at 0, with vigorous stirring, 48 mg of sodiumhydroxide in 10 ml of water. After 10 minutes the solution is dilutedwith more chloroform, the organic phase separated, washed with saturatedaqueous sodium chloride solution until neutral, dried with magnesiumsulphate, concentrated in vacuum, and the residue chromatographed inethylacetate on silica gel. In this manner are obtained 186 mg of3B,20-diacetoxy-14B- hydroxyl 8-( N-methyl-2-chloroacetariiido 501,17a-pregnane, M.P. l94-196.1R: 3380 broad, 1730, 1640, 1250.

150 mg of 3B,20-diacetoxy-14B-hydroxy-l8-(N-methyl-Z-chloroacetamido)-5a,17a-pregnane are dissolved in 18 ml ofabsolute tetrahydrofuran and 18 ml of absolute benzene; to the obtainedsolution are added, one after the other, mg of sodium hy dride and 0.3ml of a solution of 160 mg of ethanol in ml of absolute tetrahydrofuran.The mixture is stirred for 3 hours at 50; to the reaction mixture isthen added ethyl acetate, and the whole washed until'neutral withsaturated aqueous sodium chloride solution. The crude product remainingbehind afterconcentration by evaporation is chromatographed in ethylacetate on silica gel. By this means are obtained mg ofl-methyl-2'-.oxo-3B,20- diacetoxy-14B,l8-(epoxyethanoimino)-5a,17apregnane. After two crystallizations fromacetone/- hexane, the melting point is 251252. IR: 1730, 1650, 1250. [Ml00 (0.46).

100 mg of l-methyl-2'-oxo-3B,20-diacetoxy-146,18-(epoxyethanoimino)-5a,17a-pregnane are refluxed with 300 mg offreshly sublimated phosphorus pentasulphide, in a nitrogen atmosphere,in 8 ml of abs. pyridine for 3 hours. The mixture is then cooled andallowed to stand for 3 hours at room temperature; an amount of 40 ml ofmethylene chloride is afterwards added and the whole stirred for afurther 15 minutes at room temperature. The mixture is subsequentlydiluted with further methylene chloride, washed twice with saturatedaqueous sodium chloride solution, dried with magnesium sulphate, andconcentrated in vacuo. In this manner are obtained 92mg of l'-methyl-2'-thioxo-3B,20-diacetoxy-l413,18-(epoxyethanoimino)-5a,l7a-pregnane HR:1730, 1515, 1- 2501, which is further used without purification.

EXAMPLE 5 The l-methyl-2-thioxo-3B-methoxy-3a, 9a-epoxy-20-diacetoxy-14,B,-l 8-(epoxyethanommino)-5B,l 7apregnane, used asstarting material in Example 2, can

be produced as follows:

a. 10 g of (20R)-3-ethy1enedioxy-20-hydroxy-A tions yield 2.0 g ofunmodified (20R)-3 oxo-18.20- dihydroxy-A -5}9-pregnene.

1.5 g of (20R)-3-oxo-18-acetoxy-20-hydroxy- A -5B-pregnene in 100 ml ofacetone are oxig of (20R)-3-oxo-1 8-acetoxy-20-hydroxy-N""-513- pregnenewhich, after crystallization from methylene chloride/hexane, melts at110. [mi

(0.48). IR: 3580, 1730, 1710, 1250. Further fracpfegTladien-ls-acid139101164 are boiled in dized at room temperature while stirring with an300 m] of absolute r hydrofuran with 7 g of lithexcess of an 8 Nsolution of chromium trioxide in um alum nium hydride for 2 s- Then th611- 8 N sulphuric acid for minutes. Then 5 ml of cess hydride isdecomposed with about 5 ml of methanol are added, the mixture is dilutedwith urated aqueous ammonium sulphate solution while th l et t d th oganic phase is washed with cooling with g of Celite 8 added andsaturated aqueous sodium chloride solution. After t rred for 30 minutesat room mp r r the drying and concentration by evaporation, 1.49 g ofuminium hydroxide/Celite mixture is removed by crude product areobtained which, dissolved in difiltration, rinsed with ethyl acetate,and the filtrate chloromethane, is filtered through neutral aluminisconcentrated by evaporation in vacuum to yield ium oxide (Act. 111). Itis then crystallized from 9.7 g of(20R)-3-ethylenedioxy-l8,20-dihydr0xy- 15 acetone/hexane to yield 1.4 gof 3,20-dioxo l8- A -pregnadiene which, after a crystallizationacetoxy-A "-SB-pregnene, MP; 112-1l4. [al from methylenechloride/hexane, melts at 201. 7 =+67(0.48).1R: 1745, 1720, 1710, 1230(CC1.,). [al -35 (0.49). IR 3600, 3500-3200. f. 1.2 g of osmiumtetroxide are added to 1.15 g of 3,-

b. 10.7 g of (20R)-3-ethy1enedioxy-l8,20-dihydroxy-20-dioxo-l8-acetoxy-A "-SB-pregnene in 15 ml of A -pregnadiene arerefluxed for2 hours in 20 pyridine and allowed to stand for 6% days inthe 1500 ml of acetone and 100 ml of water with 1.5 dark at roomtemperature. Then the reaction mixg of p-toluene-sulphonic acid. Thereaction soluture is evaporated to dryness in vacuum with the tion isthen concentrated under vacuum to about repeated addition of benzene;the residue is dis- 500 ml. By careful addition of water to thissolusolved in 40 ml of freshly distilled dioxane. Then 40 tion, thedesired (20R)-3-oxo-18,20-dihydroxym1 of saturated, aqueous ammoniumchloride solu- A"' -pregnadiene precipitates as crystals. These tion areadded and hydrogen sulphide is passed are then suction filtered, washedneutral with a through the two-phase system during one hour. 6 largeamount of water, dried, and recrystallized g of shredded filter paperare added. After heating once from methanol/water to yield 7 g ofcrystals for one hour at 70, the mixture is filtered through having amelting point of 194. [01],, =+59 (0.61). Celite and then successivelywashed with 500 ml of IR: 3600, 3550-3100, 1660, 1615. UV: 244 ethylacetate, 100 ml ofmethanol, 100 ml of water, (16700). 100 ml ofdichloromethane and again 500 ml of 7 g of (20R)-3-oxo-l8,20-dihydroxy-A ethyl acetate. The filtrate is diluted with more ethylpregnadiene are hydrogenated in 250 ml of 0.1 N acetate and washedseveral times with saturated, ethanolic potassium hydroxide solution inthe presaqueous ammonium chloride solution. Then the ence of l g of 5percent palladium/charcoal cataorganic phase is dried with magnesiumsulphate lyst with one equivalent of hydrogen. After the calandconcentrated by evaporation in vacuum. 1.23 culated amount of hydrogenhas been taken up, the a g of crude product are obtained which, in ethylhydrogenation is interrupted, and the catalyst is re- 40acetate/methanol solution (9:1), is chromatomoved from the solvent byfiltration. By the careful graphed on silica gel to yield 1.13 g of313,110:-

, addition of water to the filtrate, (20R)-3-oxo- Idihydroxy-3a,9a-epoxy-l8-acetoxy-20-oxo-5B- 18,20-dihydroxy-A"-SB-pregnene precipitates as pregnane 11R: 3600-3200, 1740, 1710, 1230(CC1- crystals. After suction filtration, washing neutral l, which isfurther processed without purification. with a large amount of water,drying in vacuum and g. 775 mg of 3B,] la-dihydroxy-3a,9a-epoxy- 1 8-recrystallization from methanol/water, 6.7 g ofacetoxy-20-oxo-5B-pregnane in 30 mlof 0.1 N abpure crystallizationproduct having a melting point solute methanolic hydrogen chloridesolution are of 198 are obtained. [a1 D 2 (0.49). IR: 3600, left for 20minutes at room temperature. Then the 3550-3200, 1705. I mixture ispoured onto asaturated, aqueous sod. 5.1 g of(20R)-3-oxo-l8,20-dihydroxy-A -5l3- dium bicarbonate solution, extractedwith ethyl acpregnene in 60 ml'of pyridine and 40 ml of acetanetate, andthe resulting organic phase is washed hydride are allowed to stand forone hour at room several times with saturated, aqueous sodiumtemperature. Then the excess acetanhydride is dechloride solution. Afterdrying the solution with composed by the careful addition of 80 ml ofmethmagnesium sulphate and concentration by evapoanol, the temperaturebeing kept at about 0 by the ration, the crude product obtained (745 mg)is addition of solid carbon dioxide in portions. Then acetylated in 30ml of acetanhydride/pyridine mixthe reaction mixture is left to standfor 30 minutes ture (1:1) for 3% hours at 70. The reaction mixat roomtemperature, evaporated in vacuum, and ture is then concentrated byevaporation in vacthe crude product is chromatographed in benuum, andthe crude product obtained is filtered in zene/ethyl acetate 1:1) onsilica gel. First 1.5 g of dichloromethane on neutral aluminium oxide(Act. (20R)-3-oxo-18,20-diacetoxy-A "-5B-pregnene 111) to yield 805 mgof 3B-methoxy-3a,9a-epoxy- [1R2 1740-1700, 12501, which can bereconverted 1 101,18-diacetoxy-20-ox0-5B-pregnane which, into thestarting material for the acetylation by alafter one crystallizationfrom acetone/hexane, kaline hydrolysis in 5 percent methanolicpotasmelts at 15l-152. [a] =+l06(0.46). IR: 1735, sium hydroxidesolution. Later fractions yield 2.1 5 1705, 1245.

h. 500 mg of 3B-methoxy-3a,9a-epoxy-l101,18-

diacetoxy-ZO-oxo-SB-pregnane in 40 ml of carbon tetrachloride are boiledfor one hour with 208 mg of finely pulverized 96 percent N-bromosuccinimide and 10 mg of azabisisobutyronitrile while irradiatingexternally with a 1,000 W incandescent lamp. After cooling, theprecipitated succinimide is removed by filtration, rinsed with carbontetrachloride, and the filtrate is concentrated by evaporation invacuum. The resultant bromination product, without purification, isheated at 120 for 160 minutes under a nitrogen atmosphere in 40 ml ofabsolute dimethyl formamide with 500 mg of lithium carbonate and 500 mgof lithium bromide. The mixture is then diluted with a large amount ofethyl acetate, and the organic phase is washed at least times withwater. After drying and evaporating the ethyl acetate phase, 488 mg ofcrystals are obtained which, in dichloromethane, are filtered on neutralaluminium oxide (Act. Ill) to yield 435 mg of 3B-methoxy-3a,9aepoxy-l1a,] 8-diacetoxy-20-oxo-A -SB-pregnene which, after crystallizing twice(307 mg), melts at 16.7 168". [al +61 (0.53). 1R: 1730, 1668, 1590,1245. UV: 237 (8750). After chromatography of the mother liquor inhexane/acetone solution (3:1) on silica gel and subsequentcrystallization from acetone/hexane, 37 mg more of the product can beobtained. 500 mg of 3B-methoxy-3at,90t-epoxy-l101,18- diacetoxy-20-oxo-A-5B-pregnene in 150 ml of carbon tetrachloride are boiled for 17 minuteswith 240 mg of 96 percent N-bromosuccinimide and 20 mg ofaza-bis-isobutyronitrile while irradiating externally with a 1,000 Wincandescent lamp. After cooling, the precipitated succinimide isremoved by filtration. After concentration of the-filtrate byevaporation, the residue obtained is dissolved in 50 ml of absolutedimethyl formamide and heated under nitrogen for minutes at 130 whilestirring with 500 mg oflithium bromide and 500 mg oflithium carbonate.The mixture is then substantially concentrated in vacuum, diluted withethyl acetate, and washed several times with water. After drying andconcentration by evaporation of the organic phase, the crude productobtained is chromatographed in benzene/ethyl acetate solution (2:1) onsilica gel to yield 330 mg of 3l3-methoxy-3a,9a-epoxy-l 101,18-diacetoxy-20- oxo-A SB-pregnadiene which, after crystallizing oncefrom acetone/hexane, melts at l46-147. [a|,,=+302 (0.50). IR: 1730,1645, 1525, 1465,

250 mg of 3B-methoxy-3a,9a-epoxy-l la,l8-diacetoxy-ZO-oxo-A--5B-pregnadiene which has been purified bychromatography but not recrystallized, are boiled for 80 minutes with500 mg of pnitro-perbenzoic acid in a mixture of 100 ml of chloroformand 1 ml of absolute methanol. The mixture is then diluted with ethylacetate, and successively washed with ice-cold, aqueous solutions ofsodium iodide, sodium thiosulphate, sodium chloride, sodium bicarbonateand again sodium chloride. After concentration of the organic phase byevaporation, the crude product obtained is chromatographed inhexane/acetone solution (2:1) on silica gel to yield 210 mg of3B-methoxy- 301,901: 1 4B, 1 SB-diepoxy-l 1a,1 8-diacetoxy-20-oxo- A'-SB-Pregnene which, after crystallizing three times from acetone/hexane,melts at 198. [011 +66 (0.58). 1R: 1735, 1670, 1605, 1240. UV: 248(6890).

mg of 3B-methoxy-3a,9a:l4fl,lSB-diepoxyl l01,18-diacetoxy-ZO-oxo-A'-SB-pregnene in 20 ml of ethanol are thoroughly hydrogenated in thepresence of 40 mg of 5 percent palladium on barium sulphate. Then thecatalyst is removed by filtration. Chromatography in benzene/ethylacetate solution (1:1) on silica gel yields 55 mg of 3Bmethoxy-3a,9a-epoxy- 1 1a,1 8-diacetoxy- 1 4B-hydroxy-20-oxo-5B,17a-pregnane which, after crystallizing once fromacetone/hexane, melts at 154. [al 0 (0.40). IR: 3600, 3400 broad, 1735,1705, 1245. 200 mg of sodium boro-hydride in 1 ml of water are added atroom temperature to 197 mg of 3B- methoxy-3a,9a-epoxy-l1a,18-diacetoxy-14B- hydroxy-20-oxo-5B,l7a-pregnane in 10 ml ofmethanol. The mixture is then stirred for 20 minutes at roomtemperature, diluted with a large amount of ethyl acetate, and theresulting organic phase is washed neutral with saturated, aqueous sodiumchloride solution. It is then dried with magne sium sulphate andevaporated in vacuum. The resultant crude product is acetylated in 20 m1of pyridine/acetanhydride mixture (1:1 )for 3 hours at room temperature,then evaporated in vacuum and chromatographed in benzene/ethyl acetatesolution (1:1) on silica gel, whereby 172 mg of 3B-methoxy-3a,9a-epoxy-l101,18, 20lf-triacetoxy-14/3-hydroxy-5/3,l 7a-pregnane are eluted. Aftercrystallizing twice from acetone/hexane, it melts at [a|,,= +7'(0.3l).IR: 3570,

m. 132 mg of 3B-methoxy-3a,9a-epoxy-l 1a,l8,20-

triacetoxy-14l3-hydroxy-5,8, l 7a-pregnane are boiled for 7 minutes in18 ml of a 0.1 percent sodium bicarbonate solution in 90 percent aqueousmethanol. The reaction solution is then poured onto ice, immediatelyextracted with ethyl acetate, and the organic phase is washed neutralwith saturated, aqueous sodium chloride solution. After drying andconcentrating by evaporation of the ethyl acetate phase, the crudeproduct obtained is chromatographed in benzene/ethyl acetate solution1:1 on silica gel to yield, besides 18 mg of starting material, 83 mg of3B-methoxy-3a,9a-epoxy- 1 la,20-diacetoxy 14B, 1 S-dihydroxy-SB, 17apregnane which, after crystallizing once from acetone/hexane, melts at203205. Ital ==2 (0-.

.47). IR: 3600, 3460 broad, 1725, 1250. I

90 mg of 3B-methoxy-3a,9a-epoxy-l101,205- diacetoxy- 14B, 18-dihydroxy-5B,l 7a-pregnane in 10 ml of acetone are oxidized at 0 withstirring for 3 minutes with a slight excess of an 8 N solution ofchromium-trioxide in 8 N aqueous sulphuric acid (0.35 ml). Then theexcess chromium trioxide is decomposed by the addition of isopropanol,the mixture is diluted with ethyl acetate, and washed neutral as quicklyas possible with saturated, aqueous, sodium chloride solution. Afterdrying and concentration by evaporation of the ethyl acetate phase, theresulting crude product is chromatographed in benzene/ethyl acetatesolution (1:1) on silica gel to yield 62 mg of 3B-methoxy-3a,9aepoxy-11a,20-diacetoxy-14B-hydroxy-l 8-oxo- 5B,l7a-pregnane which, aftercrystallizing once from acetone/hexane, melts at 209. [01],; ='+13(0.40). IR: 3580, 3450, 2730, 1730, 1705,1250. er 3d-methoxy-3,9 iepoxy-T161,205-

diacetoxy- 1 4fl-hydroxy- 1 8-oxo-5B, 1 7a-pregnane are heated with 1 mlof methylamine in ml of absolute benzene for hours in a closed tube at120. After evaporating in vacuum, the residue is dissolved in 10 ml ofacetanhydride/pyridine mixture (1:1), then left for 3 hours at roomtemperature and concentrated by evaporation in vacuum. 67 mg of3B-methoxy-3a,9a-epoxy-l101,205- diacetoxyl 4B-hydroxy-1 8-methylimino-5,8, 1 7apregnane are obtained. IR: 3200 broad, 1725, 1665, 1250.

p. The methylimino compound obtained according to (0) is reduced in 10ml of methanol with 75 mg of sodium boro-hydride in 1 ml of water forminutes at room temperature. Then ethyl acetate is added to the reactionmixture which is then washed neutral with saturated, aqueous sodiumchloride solution, and concentrated by evaporation. 60 mg of3B-methoxy-3a,9a-epoxy-1 1a,20-diacetoxy- 14B-hydroxyl8-methylamino-5B,17a-pregnane are obtained. 1R: 3500-2600, 2790, 1725,1250.

q. The methylamino compound obtained according to (p) is dissolvedtogether with 77 mg of chloroacetyl chloride in 10 ml of chloroform.While stirring vigorously, 28 mg of sodium hydroxide in 2 ml of waterare added at 0. After 10 minutes, the solution is diluted with ethylacetate, the organic phase is separated, washed neutral with saturated,aqueous sodium chloride solution, dried with magnesium sulphate,evaporated in vacuum, and the residue is chromatographed in ethylacetate on silica gel to yield 42 mg of 3B-methoxy-3a,9a-epoxy- 1la,20-diacetoxy-14B-hydroxy-1 8-( N-methyl-2'chloracetamide)-5B,17a-pregnane which, after crystallizing once fromacetone/hexane, melts at 173. [al +12 (0.42). 1Rz3350 broad, 1725, 1640,1250.

33 mg of 3B-methoxy-3a,9a-epoxy-1 101,205- diacetoxy-14B-hydroxyl 8-(N-methyl-Z- chloracetamido)-5B,17a-pregnane are dissolved in 3 ml ofabsolute tetrahydrofuran and 3 ml of absolute benzene; first 20 mg ofsodium hydride and then 0.1 ml of a solution of 160 mg of ethanol in 100ml of absolute tetrahydrofuran are added. The mixture is boiled for 4hours under an argon atmosphere. The excess sodium hydride is thencarefully decomposed by the addition of moist ether. Then the reactionmixture is diluted with ethyl acetate and washed neutral with saturatedaqueous sodium chloride solution. After concentration by evaporation,the residual crude product is chromatographed in ethyl acetate on silicagel. 26 mg of 1'- methyl-2 -oxo-3B-methoxy-3a,9a-epoxy-l 101,205-diacetoxy-l413,18-(epoxyethanoimino)-5B,l7apregnane is obtained which,after recrystallizing once from acetone/hexane, melts at 239-240. [a|=-64 (0.25). IR: 1725, 1650, 1250.

. An amount of 100 mg of l-methyl- 2-oxo-3B- methoxy-3a,9a-epoxylla,20-diacetoxy- 1 413,1 8- (epoxyethanoimino)-5B, 17a-pregnane isreacted, analogously to Example 4 o), with 300 mg of phosphoruspentasulphide. In this way are obtained 84 mg ofl'-methyl-2-thioxo-3B-methoxy-3a,9aepoxy-1 la,20-diacetoxy- 145,18-(epoxyethanoimino)-5B,17a-pregnane [IR: 1730, 1515, 1245, 1060,1010,960, 920 which rsfamierp'mcessed without purification.

EXAMPLE 6 An amount of 40 mg of l-methyl-2-thioxo-l7B- acetoxy-SB, l 9-(epoxyethanoimino )-androstane (cp. Example 7) is stirred in 5 ml ofabsolute acetone with ca. 500 mg of deactivated Raney nickel(deactivated by being washed eight times with acetone) for 15 minutes atroom temperature. The mixture is filtered through Celite (trade-name ofJohns Manville lntemational Corps., New York), concentrated in vacuo,and chromatographed in ethyl acetate/methanol solution (9:1) on silicagel. In this manner are eluted 35 mg of 1'-methyl-17B-acetoxy-5B,19-(epoxyethanoimino)- androstane which, after onecrystallisation from methanol/water, melts at l22-l 23. [or] D 46 (0.44in Cl-lCl IR: 1730, 1250 cm.

EXAMPLE 7 The thiolactam used in the Example 6 can be produced asfollows:

a. To 4 g of 3-oxo-l7fi,l9-diacetoxy-A -androstene in 60 ml ofmethanol/methylene chloride-(2:1)- mixture are added simultaneously,whilst stirring is maintained, at 11 1 ml of 10 percent aqueous sodiumhydroxide solution and 6 ml of 30 percent aqueous hydrogen peroxidesolution. The mixture is then stirred for 3 days at 4 and ethyl acetateis added. The organic phase is separated, washed with saturated sodiumchloride solution and concentrated by evaporation. For subsequentacetylation, excess acetic anhydride/pyridine-( 1:1) is added to theresidue, the mixture allowed to stand for ca. 14 hours and thenconcentrated by evaporation in vacuo. Chromatography of the residue onsilica gel in benzene/ethyl acetate-(2:1) yields 3 g of3-oxo-4,B,5B-epoxyl 7B,19-diacetoxyandrostane, M.P. 127. [al 122 (0.21).IR: 1730-1700, 1250. g

b. To 2.2 g of 3-oxo-4B,5B-epoxy-l713,19-diacetoxyandrostane in 130 mlof ethanol are added 0.5 ml

of glacial acetic acid and 1 ml of hydrazine hydrate and the wholeallowed to stand for 30 minutes at 20. After the addition'of ethylacetate, washing is carried out with saturated sodium chloride solutionand the organic phase concentrated by evaporation in vacuo.Chromatography of the residue in benzene/ethyl acetate-(2:1) yields 1.5g of 58 hydroxy- 1 713, 1 9-diacetoxy-A -androstene, M.P. 128+129.[11],, 62 (0.45). IR: 3580, 1730,

1250. c. 100 mg of SB-hydroxy-l7fi,l9-diacetoxy-A androstene areexhaustively hydrogenated in 15 ml of ethanol in the presence of 50 mgof prehydrogenated platinum oxide catalyst.-After removal by filtrationof the catalyst, concentration and crystallisation of the crude product,mg of SB-hydroxyl7B,]9-diacetoxy-androstane, M.P. 102-l03, are obtained.[a],,=+ 6 (0.34). IR: 3590, 1730, 1250.

mg of SB-hydroxy-17B,l9-diacetoxyandrostane are boiled for 25 minutes ina mixture of 22 ml of methanol and 2.55 ml of 1 percent aqueous sodiumbicarbonate solution. After the addition of ethyl acetate, washing withsaturated so dium chloride solution, concentration byevaporzp tioii ofth organic phase and chromatography of the residue in benzene/ethylacetate-(2:1) on silica gel, 60 mg of5B,l9-dihydroxy-17B-acetoxyandrostane, M.P. l98l99, are obtained. [ad-18 (0.49). IR: 3590, 3440 (broad), i725, 1250.

100 mg of B,l9-dihydroxy-17B-acetoxyandrostane are added to a suspensionof 5 g of silver carbonate on Celite (for method cp. M. Fetizon and M.Golfier, CR. 267, 900 1968)) in ml of abs. benzene, dewatering isadditionally carried out by azeotropic distilling off of ca. 5 ml ofbenzene and refluxing is performed for 3 hours. This is followed byfiltration through Celitc, subsequent washing with benzene,concentration by evaporation in vacuo and crystallisation once fromacetone/hexane of the obtained SB-hydroxy-l 7B-acetoxy-19-oxo'androstane (90 mg). M.P. 149 with decomposition. [a]11(0.57).1R: 3590, 2740, 1730, 1250.

is heated with ml of methylamine in 100 ml of anhydrous benzene for 15hours in a bomb-tube to 120. Concentration by evaporation in vacuo isthen perfomied, whereby 1.1 g of crystalline SB- hydroxy- 1 7B-acetoxyl9-(methy1imino)- androstane are obtained [1R2 3250 (broad), 2770 (CH-N=), 1730, 1660, 12501.3, This methylimino compound obtained accordingto f) is reduced in 10 ml of methanol with 1 g of sodium borohydride in3 ml of water at 20 for minutes. Ethyl acetate is then added to thereaction mixture, the whole thoroughly washed neutral with saturatedsodium chloride solution and concentrated by evaporation, whereby 970 mgof crystalline SB-hydroxy-HB- acetoxy-l9-(methylamino)-androstane areobtained HR: 3300 2600, 1730, 1250].

h. The methylamino compound obtained according to g) is dissolved,together with 750 mg of chloroacetyl chloride, in 30 ml of chloroform.With vigorous stirring, 235 mg of sodium hydroxide in 6 ml of water areadded at room temperature. The organic phase is separated after 10minutes, washed with saturated sodium chloride solution, concentrated byevaporation in vacuo and the residue chromatographed on silica gel inethyl acetate. By this means are obtained 850 mg of5B-hydroxy-17B-acetoxyl9-(N-methyl-2-chloroacetamido)-androstane,

M.P. 2l8220. [11],, 52 (0.50). IR: 3360,

'. 210 mg of SB-hydroxy-17B-acetoxy-19-(N-methyl-2-chloroacetamido)-androstane are dissolved in 5 ml of anhydroustetrahydrofuran and 5 ml of anhydrous benzene; and to this solution aresuccessively added mg of sodium hydride and 0.02 ml of a solution of 0.1ml of ethanol in 2 ml of anhydrous tetrahydrofuran. The mixture isstirred for 30 minutes at 20 and then for 30 minutes at Ethyl acetate isadded to the reaction mixture and the latter washed neutral withsaturated sodium chloride solution. The crude product, obtained afterconcentration by evaporation in vacuo of the organic phase, ischromatographed in ethyl acetate on silica gel. Firstly obtained are 138mg of 1'-methyl- 2'-oxol 7B-acetoxy-5fi, l 9-( epoxyethanoimino)-androstane with M.P., after two crystallisations from acetone/hexane] 931948 a +78(0.- 31). IR: 1730, 1645, 1250.

Subsequent fractions yield 17 mg of l-methyl- 2'- oxo-l 7 B-hydroxy-SB,l 9-( epoxyethanoimino androstane, M.P. 258260. [0:1 84 (0.28). IR:3590, 1645.

To effect the conversion of the l7B-hydroxy compound obtained asby-product into the main product,

1 g of 5B-hydroxy-l7Bacetoxy-l9-oxo-androstane the by-product isdissolved in 2 ml of acetic anhydride/- pyridine (1:1), and the solutionallowed to stand for 15 hours at room temperature. The solution is thenconcentrated in vacuo and the residue recrystallised fromacetone/hexane. In this manner are obtained a further 15 mg ofl-methyl-2-oxo-17B-acetoxy-5B,19-(epoxyethanoimino)-androstane, M.P.l93-194. Identification with the main product of 1') according to M.P.of mixture, lR-spectrum and thin-layer chromatogram.

j. An amount of 50 mg of l'-methyl-2'-oxo-l78acetoxy-SB,19-(epoxyethanoimino)-androstane is refluxed with 150 mg offreshly sublirnated phosphorus pentasulphide, in a nitrogen atmosphere,in 4 ml of absolute pyridine for 2 hours. The mixture is then cooled,allowed to stand at room temperature for a further 2 hours, 20 ml ofmethylene chloride are added and stirring is carried out at roomtemperature for a further 15 minutes. The reaction mixture issubsequently diluted with a large amount of methylene chloride, washedtwice with saturated aqueous sodium chloride solution, dried wihmagnesium sulphate, and concentrated in vacuo. Chromatography on silicagel in beniene/ethyl acetate solution (9:1) yields 49 mg of 1-methyl-2'-thioxo-17,8-acetoxy-5B,l9-(epoxyethanoimino)-androstane whichmelts, after crystallisation from acetone/hexane (47 mg), at 20320- 4.[dl =+78" (0.75 in CHCl 1R: 1730, 1520, 1255, 1065, 1050 cm".

What we claim is:

1. Process for the production of 14,8, 18- and 56,

l9-(epoxyethanoimino) steroids of the general formula wherein Rrepresents lower alkyl, benzyl or hydrogen, and

one of the symbols Y and Z represents an aliphatic radical and the othera binuclear cycloaliphatic radical which together complete formula 1 toformula la with lower alkanoic acids or hydroxyl etherified with loweralkanols, Z-tetrahydropyranol, benzyl alcohol, triphenylmethyl alcohol,4-methoxy-4- tetrahydropyranol, l l -methoxy-cyclohexanol and a hydrogenatom, or an etherified hydroxyl group as above and together with R anepoxy radical R and R each independently represent a protected oxo'radical derived from lower alkane-diols or an hydroxyl group csterificdwith lower alkanoic acids or hydroxyl etherified with lower alkanols, 2-tetrahydropyranol, benzyl alcohol, triphenylmethyl alcohol,4-methoxy-4-tetrahydropyranol, 1 ,lmethoxy-cyclo-hexanol and a hydrogenatom, or two hydrogen atoms, or, when occurring at a double bond, onehydrogen atom R represents aor B-oriented hydrogen, R representsa-oriented hydrogen, a-oriented hydroxyl, or together with R epoxy, andR represents aor B-oriented hydrogen, or an esterifled or etherifiedhydroxyl group, as above whereby double bonds may be present in thepositions 5, 7, 9 (l 1) corresponding to the dotted lines with theelimination of R R and/or R or to formula lb, I

wherein Y R has the meaning given under formula I, and

R represents a protected oxo radical as above or an esterified oretherified hydroxyl group as above in the B-position together with ahydrogen atom or a lower aliphatic hydrocarbon radical whereby in theother, unoccupied positions of the steroid structure there can bepresent double bonds and/or esterified or etherified or hydroxyl groups.as above, additional methyl groups, protected oxo. radicals as above,methylene groups, or epoxy radicals as substituents, and of their acidaddition salts, wherein a compound of the general formula I] wherein R,,Y and Z have the meaning given for formula l, is reacted withRaney-Nickel in an organic solvent.

2. Process according to claim 1, wherein a compound of the generalformula Ila 3. Process according to claim 1, wherein a compound of thegeneral fermalallkwherein R, and R have the meanings given in claim 1,and substituents and double bonds may be present as specified in saidclaim, is reacted with Raney Nickel in an organic solvent.

4. Process according to claim 1, wherein a compound of the generalformula H as illustrated in claim 1, wherein R,, Y and Z have themeanings defined in said claim, is reacted with the 2- to 20-fold amountby weight of Raney Nickel in an organic solvent.

5. Process according to claim 1, wherein the reaction is carried out ata temperature between 0 to 50C.

6. Process according to claim 1, wherein ethanol, methanol or acetone isused as organic solvent.

7. Process according to claim 1, wherein the reaction is carried out atroom temperature.

8. Process according to claim 1., l '-methyl-2'-thioxo'-3B,20fi-diacetoxy- 145,

wherein (epoxyethanoimino)-5a, l7a-pregnane is used as startingmaterial. 1 w P rocess according w claim I, wherein l'-methyl-2'-thioxo-3,8-methoxy-3a, 9a-epoxy-l la, 20f-diacetoxy- 14B,l8-(epoxyethanoimino)-5B,

, l7a-pregnane is used as starting material.

claim 1, wherein l'-methyl 2-thioxol 7B-acetoxy- 5B,l9-(epoxyethanoimino)-androstane is used as starting material. 7 V

11. A member selected from the group consisting of 10'. Processaccording to wherein R,, R R R are selected from the group consisting ofhydroxy, lower alkoxy and lower alkanoyloxy, and R is a lower alkylgroup, and wherein the dotted lines indicate that in the positionsindicated there can optionally be double bonds and the wavy linesindicate 5 that both the aand B-configuration are possible, and acompound of the formula thanoimino)-androstane.

2. Process according to claim 1, wherein a compound of the generalformula IIa
 3. Process according to claim 1, wherein a compound of thegeneral formula IIb
 4. Process according to claim 1, wherein a compoundof the general formula II as illustrated in claim 1, wherein R1, Y and Zhave the meanings defined in said claim, is reacted with the 2-to20-fold amount by weight of Raney Nickel in an organic solvent. 5.Process according to claim 1, wherein the reaction is carried out at atemperature between 0* to 50*C.
 6. Process according to claim 1, whereinethanol, methanol or acetone is used as organic solvent.
 7. Processaccording to claim 1, wherein the reaction is carried out at roomtemperature.
 8. Process according to claim 1, wherein1''-methyl-2''-thioxo-3 Beta , 20 xi -diacetoxy-14 Beta ,18-(epoxyethanoimino)-5 Alpha , 17 Alpha -pregnane is used as startingmaterial.
 9. Process according to claim 1, wherein1''-methyl-2''-thioxo-3 Beta -methoxy-3 Alpha , 9 Alpha -epoxy-11 Alpha, 20 xi -diacetoxy- 14 Beta , 18-(epoxyethanoimino)-5 Beta , 17 Alpha-pregnane is used as starting material.
 10. Process according to claim1, wherein 1''-methyl 2''-thioxo-17 Beta -acetoxy-5 Beta ,19-(epoxyethanoimino)-androstane is used as starting material.
 11. Amember selected from the group consisting of a compound of the formula12. A compound according to claim 11, which is 1''-methyl-2''-thioxo-3Beta -20 xi -diacetoxy-14 Beta ,18-(epoxyethanoimino)-5 Alpha ,17 Alpha-pregnane.
 13. A compound according to claim 11, which is1''-methyl-2''-thioxo-3 Beta -methoxy-3 Alpha -9 Alpha -epoxy-11 Alpha,20 xi -diacetoxy-14 Beta ,18-(epoxyethanoimino)-5 Beta ,17 Alpha-pregnane.
 14. A compound according to claim 11, which is1''-methyl-2''-thioxo-17 Beta -acetoxy-5 Beta,19-(epoxyethanoimino)-androstane.